In North America, approximately 1 in 150 births is now derived from an [assisted reproductive technology] ART pregnancy. Recent reports of large and well-characterized populations of ART-assisted offspring note an overall risk of a major birth defect as high as 8-9%, a several fold increase over the general population. Additionally, evidence is mounting that ART may generate epigenetic mutations. Epigenetics, the modulation of gene function by methylation and/or chromatin modification, is central to imprinting. Alterations in imprinting, the process by which one copy of a gene is preferentially silenced according to parental origin is central to congenital malformations, embryonic growth and cancer. When sheep embryos are cultured, loss of imprinting for the insulin-like growth factor receptor can lead to unusually large offspring. In humans, anecdotal reports suggest an increased risk of epigenetic alterations in pregnancies conceived utilizing ART. Two recent trends in ART are of particular concern: the use of intracytoplasmic sperm injection (ICSI) and extended embryo culture in vitro. ICSI, increasingly used to treat non-specific infertility, accounts for 60%-80% of all ART procedures in some centers. Another change in procedure, prolonged in vitro culture, is the norm to maximize implantation of morphologically normal embryos. With ICSI, sperm or a spermatid injection into the oocyte results in fundamental differences from normal fertilization regarding egg activation, decondensation of sperm DNA, replication timing and orientation of male and female pronuclei. Prolonged in vitro culture presents its own problems; minor changes in media are known to affect imprinting in murine and bovine embryos. Development of a research protocol for a North American prospective study to evaluate the risk of genetic and epigenetic alterations leading to congenital malformations and cancer in offspring conceived using assisted reproductive technologies (ART) is needed.